WO2016134363A1 - Compositions comprenant du peroxyde de benzoyle ou un dérivé de celui-ci et au moins un agent antiseptique de préparation de la peau - Google Patents

Compositions comprenant du peroxyde de benzoyle ou un dérivé de celui-ci et au moins un agent antiseptique de préparation de la peau Download PDF

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Publication number
WO2016134363A1
WO2016134363A1 PCT/US2016/018918 US2016018918W WO2016134363A1 WO 2016134363 A1 WO2016134363 A1 WO 2016134363A1 US 2016018918 W US2016018918 W US 2016018918W WO 2016134363 A1 WO2016134363 A1 WO 2016134363A1
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WIPO (PCT)
Prior art keywords
skin preparation
preparation agent
chlorhexidine
alcohol
antiseptic skin
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PCT/US2016/018918
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English (en)
Inventor
Paul M. SETHI
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Sethi Paul M
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Publication of WO2016134363A1 publication Critical patent/WO2016134363A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/327—Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • pre-operative preventive measures which include skin cleansing with antiseptic skin preparation agents, such as aqueous-based (e.g., povidone-iodine) or alcohol-based (e.g., chlorhexidine-isopropanol) agents
  • skin cleansing with antiseptic skin preparation agents such as aqueous-based (e.g., povidone-iodine) or alcohol-based (e.g., chlorhexidine-isopropanol) agents
  • P. Acnes Propionibacterium Acnes
  • residual P. Acnes is found on the skin up to 29% of the time, and in 70% of dermal biopsy. These residual bacteria may be a source for infection. Identifying more ideal antiseptic skin preparation agents may help reduce the risk of infection for patients undergoing surgery, including, for example, shoulder surgery, elbow surgery, spinal surgery, and neurosurgery.
  • aqueous- or alcohol-based products containing iodophors or chlorhexidine gluconate such as, for example, aqueous-iodophor (e.g., Betadine®, Scrub Care®), aqueous-chlorhexidine gluconate (e.g., Hibiclens®), alcohol -iodophor (e.g., DuraPrep®, Prevail-FX®), and alcohol-chlorhexidine gluconate (ChloraPrep®).
  • aqueous-iodophor e.g., Betadine®, Scrub Care®
  • aqueous-chlorhexidine gluconate e.g., Hibiclens®
  • alcohol -iodophor e.g., DuraPrep®, Prevail-FX®
  • Alcohol-chlorhexidine gluconate ChloraPrep®
  • Aqueous-based iodophors such as povidone-iodine, contain iodine complexed with a solubilizing agent that allows for the release of free iodine when in solution.
  • Iodine acts in an antiseptic fashion by destroying microbial proteins and DNA.
  • 2 Iodophor- containing products enjoy widespread use because of their broad-spectrum antimicrobial properties, efficacy, and safety on nearly all skin surfaces in patients regardless of age.
  • a second product, aqueous-based chlorhexidine gluconate works by disrupting bacterial cell membranes.
  • Chlorhexidine gluconate has more sustained antimicrobial activity and is more resistant to neutralization by blood products than the iodophors. 2
  • Ethanol and isopropanol are two of the most effective antiseptic skin preparation agents available. 2 When used alone, alcohol is fast and short acting, has broad-spectrum antimicrobial activity, and is relatively inexpensive. 2 Alcohol-based solutions that contain chlorhexidine gluconate or iodophors have sustained and durable antimicrobial activity that lasts long after alcohol evaporation. 2 Studies suggest that these products may have greater efficacy, easier application, improved durability, and a superior cost profile when compared with traditional aqueous-based solutions.
  • BPO benzoyl peroxide
  • at least one antiseptic skin preparation agent such as, for example, an aqueous- based antiseptic skin preparation agent ⁇ e.g., aqueous-iodophor, aqueous-chlorhexidine gluconate) and/or an alcohol -based antiseptic skin preparation agent (e.g., alcohol -iodophor, alcohol-chlorhexidine gluconate)
  • an aqueous- based antiseptic skin preparation agent e.g., aqueous-iodophor, aqueous-chlorhexidine gluconate
  • alcohol -based antiseptic skin preparation agent e.g., alcohol -iodophor, alcohol-chlorhexidine gluconate
  • compositions and kits comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent, which may be used, for example, to reduce bacteria, such as, for example, P. Acnes on, within, and/or beneath mammalian skin (e.g., human epidermis, dermis, and/or hypodermis) during the perioperative period of an invasive procedure.
  • These compositions and kits may be, for example, antiseptic, cosmetic, dermatological, or pharmaceutical compositions.
  • the invention further relates to methods of reducing bacteria, such as, for example, P.
  • compositions comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent.
  • the invention also relates to methods of reducing bacteria, such as P.
  • a mammal e.g., a human
  • a First Composition comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and administering to said mammal a Second
  • Composition comprising, consisting of, or consisting essentially of at least one antiseptic skin preparation agent.
  • an antiseptic skin preparation agent means one or more antiseptic skin preparation agents.
  • P. Acnes a gram-positive anaerobic bacillus, resides nonpathogenically in the sebaceous glands associated with hair follicles, but is a significant pathogen in patients undergoing surgical procedures, such as shoulder surgery, elbow surgery, spinal surgery, and neurosurgery. 5 ' 6 ' 7 Infection following surgical procedures, such as shoulder surgery, has serious impact on patient outcome, costs, and value associated with care. When it is unrecognized or untreated in the case of shoulder surgery, indolent infection with P. Acnes may result in persistent shoulder pain and glenohumeral arthrosis, sometimes many years after the index procedure. 25 The diagnosis of P.
  • Chlorhexidine gluconate combined with isopropyl alcohol has been suggested to be the most effective surgical skin preparation for shoulder surgery, but this effect is not specific for P. Acnes. 14 ' 23 ' 24 P. Acnes may persist on the skin from 7 to 29% of the time immediately following skin preparation. 12, 19 ' 24 This may increase to 41 to 63% chance of finding this bacteria at the end of the surgical procedure. 25 Furthermore, P. Acnes was identified in 70%) of subjects undergoing a dermal biopsy after skin preparation with ChloraPrep®. 14 These residual bacteria may be present because current skin preparations appear to not sufficiently penetrate the dermal layer of skin, where P. Acnes resides in the sebaceous glands. 18 Alternately, P. Acnes may reside in the normal shoulder, or may even be a precursor pathologic organism to developing arthritis. 15
  • the high rate of residual bacteria left on the epidermis and dermis both may be the source of infection in susceptible patients, particularly those having procedures with a surgical implant. 18 A more ideal surgical skin preparation to address the residual bacteria and potentially reduce the risk for SSI is, therefore, needed.
  • benzoyl peroxide (BPO) has been an important component of topical therapy for acne vulgaris for more than five decades due to its ability to markedly reduce P. Acnes. 3 ' 8 ' 9 ' 16 ' 17
  • the invention disclosed herein used dermatologic principles of reducing P. Acnes as part of the surgical skin preparation.
  • the invention provides compositions comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent, which may be used, for example, to reduce bacteria, such as, for example, P. Acnes, in mammalian skin ⁇ e.g., human skin) during the perioperative period of an invasive procedure.
  • at least one antiseptic skin preparation agent which may be used, for example, to reduce bacteria, such as, for example, P. Acnes, in mammalian skin ⁇ e.g., human skin
  • the benzoyl peroxide or a derivative thereof may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the composition.
  • Derivatives of benzoyl peroxide include, but are not limited to, compounds of Formula (I) being independently substituted by one to five substitutions on at least one of the benzene rings, with a substituent selected from Ci-C 6 alkyl, C2-C6 alkenyl, Ci-C 6 alkynyl, and Ci-C 6 cycloalkyl.
  • the at least one antiseptic skin preparation agent may be selected from, for example, an aqueous-based antiseptic skin preparation agent, an alcohol-based antiseptic skin preparation agent, or mixtures thereof.
  • the aqueous-based antiseptic skin preparation agent may be selected from, for example, an aqueous-iodophor antiseptic skin preparation agent and an aqueous-chlorhexidine antiseptic skin preparation agent.
  • iodophor means a composition comprising iodine complexes with a solubilizing agent, such as, for example, a surfactant or povidone.
  • the iodophor in the aqueous-iodophor antiseptic skin preparation may be selected from, for example, povidone-iodine.
  • the iodine in the aqueous-iodophor antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%), and most preferably about 0.75 - 5 wt.%>, in each case based on the total weight of the composition.
  • the aqueous-iodophor antiseptic skin preparation agent may be, for example, Betadine® or Scrub Care®.
  • the chlorhexidine in the aqueous- chlorhexidine antiseptic skin preparation agent may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate.
  • the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.%, in each case based on the total weight of the composition.
  • the aqueous-chlorhexidine antiseptic skin preparation agent may be, for example, Hibiclens®.
  • the alcohol-based antiseptic skin preparation agent may be selected from, for example, an alcohol -iodophor antiseptic skin preparation agent and an alcohol-chlorhexidine antiseptic skin preparation agent.
  • the iodophor in the alcohol -iodophor antiseptic skin preparation may be selected from, for example, povidone- iodine.
  • the iodine in the alcohol-iodophor antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 0.7 - 0.8 wt.%, in each case based on the total weight of the composition.
  • the alcohol-iodophor antiseptic skin preparation agent may be, for example, DuraPrep® or Prevail-FX®.
  • the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate.
  • the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent may be present in the composition of the invention in an amount ranging from, for example, 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.%, in each case based on the total weight of the composition.
  • the alcohol-chlorhexidine antiseptic skin preparation agent may be, for example, ChloraPrep®.
  • the alcohol in the alcohol- iodophor and alcohol-chlorhexidine antiseptic skin preparation agents may be selected from, for example, at least one monohydric alcohol, such as, for example, methanol, ethanol, isopropanol, butanol, and pentanol, at least one polyhydric alcohol, such as, for example, ethylene glycol, propylene glycol, glycerol, erythritol, and xylitol, or mixtures thereof.
  • at least one monohydric alcohol such as, for example, methanol, ethanol, isopropanol, butanol, and pentanol
  • at least one polyhydric alcohol such as, for example, ethylene glycol, propylene glycol, glycerol, erythritol, and xylitol, or mixtures thereof.
  • the alcohol is preferably an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n- butanol, isobutanol, t-butanol, or glycerol, most preferably isopropanol.
  • the alcohol in the alcohol -iodophor and the alcohol-chlorhexidine antiseptic skin preparation agents may be present in the composition of the invention in an amount ranging from, for example, about 50 - 90 wt.%, more preferably about 60 - 80 wt.%, and most preferably about 70 - 75 wt.%, in each case based on the total weight of the composition.
  • the composition of the invention may also include at least one additional active ingredient, such as, for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, and mixtures thereof.
  • the at least one additional active ingredient may be selected from an antibiotic, including, without limitation, erythromycin, clindamycin, tetracycline, and cefazoline, preferably clindamycin.
  • the at least one additional active ingredient may be present in the composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the composition.
  • compositions of the invention may be formulated together with at least one pharmaceutically acceptable excipient, filler, extender, binder, humectant, disintegrating agent, solution retarder, absorption accelerator, wetting agent, adsorbent, lubricant, buffering agent, carrier, diluent, adjuvant, emollient, emulsifier, wax, solubilizer, electrolyte, hydroxyacid, stabilizer, cationic polymer, film former, thickener, gelling agent, superfattening agent, refattening agent, antimicrobial active compound, biogenic active compound, astringent, deodorizing compound, antioxidant, moisturizer, solvent, colorant, pearlizing agent, fragrance, opacifier, silicone, or mixtures thereof.
  • the compositions of the invention may be prepared by methods known in the pharmaceutical formulation art, for example, see Remington's
  • compositions of the invention are present in the form of fluids, gels, foams, sprays, lotions, or creams.
  • compositions are formulated on an aqueous or aqueous-alcoholic basis or are present as solutions, emulsions, or dispersions.
  • a composition of the invention comprises, consists of, or consists essentially of benzoyl peroxide, chlorhexidine gluconate, and isopropanol.
  • the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent of the invention may be separately administered, simultaneously or sequentially, for example, during the perioperative period of an invasive procedure.
  • administered sequentially refers to ordered and successive administration of a composition of the invention or their components comprised in separate containers.
  • a topical composition of the invention may be applied once, twice, three times a day, or more.
  • the order of addition of the components of the composition may be optional.
  • the invention further provides a kit comprising at least one container comprising, consisting of, or consisting essentially of at least one component of the invention; and instructions for administration of said containers.
  • the invention provides a kit comprising: a first container comprising, consisting of, or consisting essentially of at least one component of the invention; a second container comprising, consisting of, or consisting essentially of at least one component of the invention; and instructions for administration of said containers.
  • the invention provides a kit comprising at least one container comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof and at least one antiseptic skin preparation agent of the invention.
  • a first container of the kit may comprise, consist of, or consist essentially of benzoyl peroxide or a derivative thereof
  • a second container of the kit may comprise, consist of, or consist essentially of at least one antiseptic skin preparation agent of the invention.
  • a kit of the invention comprises a first container comprising, consisting of, or consisting essentially of benzoyl peroxide and a second container comprising, consisting of, or consisting essentially of chlorhexidine gluconate and isopropanol.
  • a kit of the invention comprises a first container comprising, consisting of, or consisting essentially of benzoyl peroxide and a second container comprising, consisting of, or consisting essentially of an antiseptic where the benzoyl peroxide and antiseptic are formulated as a fluid, gel, foam, spray, lotion, or cream or present on brushes, rollers, swabs, foams (e.g., polyethylene foam) packed fibers, wipes, towel ettes, or as an aerosol and the like.
  • the antiseptic may be chlorhexidine, chlorhexidine gluconate, or chlorhexidine gluconate, and isopropanol.
  • the benzoyl peroxide and the antiseptic, such as chlorhexidine gluconate may be used in a kit in accordance with USFDA monographs regarding OTC topical acne products and OTC topical antiseptic drug products.
  • instructions when used in the context of a kit includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the kit for its designated use.
  • instructions may indicate administration of a first container on non-consecutive days and for administration of a second container daily.
  • the instructions can, for example, be affixed to or included within a container for the kit.
  • the components of a composition of the invention in the first and second container are the same. In other embodiments, the components of a composition of the invention in the first and second container are different. In a further embodiment, the
  • components of a composition of the invention may be comprised in multiple, i.e., more than two, containers.
  • compatible components of a composition of the invention may be placed in one container, separated from other components of said composition.
  • each component of a composition of the invention is contained in a separate container.
  • all components for administration on a particular day are combined and stored in one container for ease of use and storage. If necessary for stability purposes, the container may be stored frozen and thawed before administration, e.g., by placing in a refrigerator one or two days before administration.
  • the term "container" as used herein refers to any receptacle or applicator means capable of holding, storing, and/or applying at least one component of a composition of the invention.
  • Such a container may be in any container configuration known to a person skilled in the art, such as, but not limited to, a swab, a pouch, a syringe, an ampoule, a bottle, a jar, a vial, or a box.
  • the containers may be made of any material suitable for the components contained therein and additionally suitable for short and/or long term storage under any kind of temperature.
  • Such material s include, by way of example, inorganic material s, such as Type I glass (including amber colored glass), ceramics, metals (e.g., aluminum, tin, and tin coated tubes), etc., and organic materials such as inert polymers including po!yo!efms (e.g., high density polyethylene), fluorinated polyolefins, and the like.
  • Suitable containers include those that maintain the sterility and integrity of their contents, for example, by providing a barrier to moisture.
  • the preferred container is also one which is compatible with any chosen method of sterilization, including, for example, irradiation.
  • the suitable containers may have an appropriate applicator means, surface, or tip to dispense the compositions of the invention from the container and apply onto mammalian skin, such as, for example, brushes, rollers, swabs, foams (e.g., polyethylene foam) packed fibers, wipes, towelettes, or as an aerosol, and the like.
  • the containers may be sealed as separate articles or are combined into a single article of manufacture having a barrier between the containers. This barrier can either be removed or destroyed allowing mixing of the components of the composition of the invention in each of the containers at the appropriate time.
  • barriers include frangible or crushable barriers or envelopes.
  • the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent are contained in at least two containers in a kit of the invention.
  • a kit of the invention is composed of a dual chamber container wherein the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent are contained in each one of the chambers.
  • a kit of the invention is for use in reducing bacteria, such as, for example, P. Acnes, in mammalian skin during the perioperative period of an invasive procedure.
  • the kit may also contain in one or more containers any of the additional components described herein, including, for example, at least one additional active ingredient, such as, for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, or mixtures thereof, and/or at least one additional active ingredient, such as, for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, or mixtures thereof, and/or at least one
  • excipient filler, extender, binder, humectant, disintegrating agent, solution retarder, absorption accelerator, wetting agent, adsorbent, lubricant, buffering agent, carrier, diluent, adjuvant, emollient, emulsifier, wax, solubilizer, electrolyte, hydroxyacid, stabilizer, cationic polymer, film former, thickener, gelling agent, superfattening agent, refattening agent, antimicrobial active compound, biogenic active compound, astringent, deodorizing compound, antioxidant, moisturizer, solvent, colorant, pearlizing agent, fragrance, opacifier, silicone, or mixtures thereof.
  • additional components may be in the same or different containers as the one or more containers comprising the benzoyl peroxide or a derivative thereof and the at least one antiseptic skin preparation agent.
  • the invention provides methods of reducing bacteria, such as, for example, P. Acnes, in mammalian skin ⁇ e.g., human skin) during the perioperative period of an invasive procedure comprising administering to a mammal ⁇ e.g., a human) in need thereof compositions of the invention described herein.
  • the invasive procedure may be a surgical procedure, such as an arthroscopic surgical procedure or an endoscopic surgical procedure.
  • the invasive procedure is shoulder and upper extremity surgery, elbow surgery, spinal surgery, neck surgery, insertion of a central venous catheter (a central line), pacemaker surgery, and neurosurgery, most preferably shoulder surgery.
  • the compositions of the invention may be administered to the mammal in need thereof before, during, and/or after the invasive procedure.
  • the invention provides methods of reducing bacteria, such as, for example, P. Acnes, in mammalian skin ⁇ e.g., human skin) during the perioperative period of an invasive procedure comprising administering to a mammal ⁇ e.g., a human) in need thereof a First Composition comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof, and administering to the mammal a Second Composition comprising, consisting of, or consisting essentially of at least one antiseptic skin preparation agent.
  • a mammal ⁇ e.g., a human
  • a First Composition comprising, consisting of, or consisting essentially of benzoyl peroxide or a derivative thereof
  • Second Composition comprising, consisting of, or consisting essentially of at least one antiseptic skin preparation agent.
  • the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal before, at the same time, and/or after the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal.
  • the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof is administered to the mammal before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal.
  • the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal, for example, at least about 12 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60 hours, and/or at least about 72 hours before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal.
  • the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal, for example, at least about 12 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60 hours, and/or at least about 72 hours before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal.
  • the First Composition comprising, consisting of, or consisting essentially of the
  • Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof may be administered to the mammal on at least one or more separate occasions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 separate times) before the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent is administered to the mammal.
  • the invasive procedure may be a surgical procedure, such as an arthroscopic surgical procedure or an endoscopic surgical procedure.
  • the invasive procedure is shoulder and upper extremity surgery, elbow surgery, spinal surgery, neck surgery, insertion of a central venous catheter (a central line), pacemaker surgery, and neurosurgery, most preferably shoulder surgery.
  • the benzoyl peroxide or a derivative thereof may be present in the First Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the First Composition.
  • the at least one antiseptic skin preparation agent in the Second Composition may be selected from, for example, an aqueous-based antiseptic skin preparation agent, an alcohol-based antiseptic skin preparation agent, or mixtures thereof.
  • the aqueous-based antiseptic skin preparation agent in the Second Composition may be selected from, for example, an aqueous-iodophor antiseptic skin preparation agent and an aqueous-chlorhexidine antiseptic skin preparation agent.
  • the iodine in the aqueous-iodophor antiseptic skin preparation agent may be present in the Second Composition an amount ranging from, for example, about 0.05% - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 0.75 - 5 wt.%, in each case based on the total weight of the Second Composition.
  • the aqueous-iodophor antiseptic skin preparation agent in the Second Composition may be, for example, Betadine® or Scrub Care®.
  • the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent in the Second Composition may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate.
  • the chlorhexidine in the aqueous-chlorhexidine antiseptic skin preparation agent may be present in the Second
  • composition of the invention in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.%, in each case based on the total weight of the Second Composition.
  • the aqueous-chlorhexidine antiseptic skin preparation agent in the Second Composition may be, for example, Hibiclens®
  • the at least one alcohol-based antiseptic skin preparation agent in the Second Composition may be selected from, for example, an alcohol -iodophor antiseptic skin preparation agent and an alcohol-chlorhexidine antiseptic skin preparation agent.
  • the iodine in the alcohol -iodophor antiseptic skin preparation agent may be present in the Second Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%), and most preferably about 0.7 - 0.8 wt.%, in each case based on the total weight of the Second Composition.
  • the alcohol -iodophor antiseptic skin preparation agent in the Second Composition may be, for example, DuraPrep® or Prevail-FX®.
  • the chlorhexidine in the alcohol-chlorhexidine antiseptic skin preparation agent in the Second Composition may be selected from, for example, chlorhexidine and a chlorhexidine salt, analog, and derivative thereof, such as, for example, chlorhexidine diacetate, chlorhexidine acetate, chlorhexidine digluconate, chlorhexidine gluconate, and chlorhexidine hydrochloride, preferably, chlorhexidine gluconate.
  • the chlorhexidine may be present in the alcohol-chlorhexidine antiseptic skin preparation agent in the Second Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2 - 4 wt.% , in each case based on the total weight of the Second Composition.
  • the alcohol-chlorhexidine antiseptic skin preparation agent in the Second Composition may be, for example, ChloraPrep®.
  • the alcohol in the alcohol-iodophor and alcohol-chlorhexidine antiseptic skin preparation agents in the Second Composition may be selected from, for example, at least one monohydric alcohol, such as, for example, methanol, ethanol, isopropanol, butanol, and pentanol, at least one polyhydric alcohol, such as, for example, ethylene glycol, propylene glycol, glycerol, erythntol, and xylitol, or mixtures thereof.
  • monohydric alcohol such as, for example, methanol, ethanol, isopropanol, butanol, and pentanol
  • at least one polyhydric alcohol such as, for example, ethylene glycol, propylene glycol, glycerol, erythntol, and xylitol, or mixtures thereof.
  • the alcohol is preferably an alcohol having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, t-butanol, or glycerol, most preferably isopropanol.
  • Composition may be present in an amount ranging from, for example, about 50 - 90 wt.%, more preferably about 60 - 80 wt.%, and most preferably about 70 - 75 wt.% , in each case based on the total weight of the Second Composition.
  • the First and/or Second Composition may further comprise at least one additional active ingredient, such as for example, a bactericidal disinfectant, a bactericidal antiseptic, a bactericidal antibiotic, an antibiotic, a retinoid, other antiseptic agents, and mixtures thereof.
  • the at least one additional active ingredient may also be optionally administered to said mammal before, during, and/or after the First Composition comprising, consisting of, or consisting essentially of the benzoyl peroxide or a derivative thereof and/or the Second Composition comprising, consisting of, or consisting essentially of the at least one antiseptic skin preparation agent are administered to said mammal.
  • the at least one additional active ingredient may be selected from an antibiotic, including, without limitation, erythromycin, clindamycin, tetracycline, and cefazoline, preferably clindamycin.
  • the at least one additional active ingredient may be present in the First and/or Second Composition in an amount ranging from, for example, about 0.05 - 15 wt.%, more preferably about 0.5 - 10 wt.%, and most preferably about 2.5 - 5 wt.%, in each case based on the total weight of the First and/or Second Composition.
  • the present invention further provides a kit comprising one or more containers comprising the Fist Composition of the invention; the Second Composition of the invention; and instructions for administration of said one or more containers.
  • the invention provides methods of treating and/or preventing a dermatological condition, such as, for example, acne, comprising administering to a mammal (e.g., a human) in need thereof (e.g., suffering from, susceptible to, and/or displaying symptoms of a dermatological condition) compositions of the invention described herein.
  • a mammal e.g., a human
  • the compositions of the invention are administered locally to an affected site (e.g., face, neck, back, arms, chest, etc.).
  • compositions of the invention and methods of treatment of the inventions described herein may be administered to the mammal in need thereof by any route accepted as appropriate by the medical community, and is not limited to any particular route.
  • routes of delivering or administering that include, but are not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, intradermal, rectal, vaginal,
  • intraperitoneal, intragastric, topical and/or transdermal e.g., by lotions, creams, liniments, ointments, powders, gels, drops, deodorants, antiperspirants, sunscreens, foams, balms, waxes, salves, solutions, suspensions, dispersions, water in oil or oil in water emulsions,
  • microemulsions pastes, oils, lozenges, boluses, and sprays, and the like
  • mucosal intranasal, buccal, enteral, vitreal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; as an oral spray, nasal spray, and/or aerosol, and/or through a portal vein catheter; and/or combinations thereof.
  • chlorhexidine gluconate ChloraPrep®; CareFusion, San Diego, California, USA. This is generally routine for all patients undergoing shoulder surgery. After preparations and draping, the skin of the anterior deltoid and axilla were each swabbed with a skin swab. A cotton swab of the air was taken at this time as a control. Each swab was placed into individual charcoal mediums. [0052] After incision for trochar placement, the glenohumeral joint was aspirated. If no fluid was available, the glenohumeral joint was flushed with five cc's of saline and then collected in a sterile specimen container.
  • the first tissue sample was collected from the middle glenohumeral ligament (MGHL). If the patient was having a rotator cuff repair, the second tissue sample came from the rotator interval and the third from the bursa. For a patient undergoing a labrum repair, the second tissue sample was collected from the high rotator interval and the third from the low rotator interval. Each sample was placed into individual specimen containers.
  • MGHL middle glenohumeral ligament
  • Each control and skin swabs were removed from their transport bag and streaked across a microscope slide to check immediately for contaminating organisms with a Gram stain.
  • the swabs were next streaked across the first quadrant of each agar plate.
  • the swabs were then placed in a test tube of thioglycollate broth to encourage the growth of any organisms present.
  • Individual, disposable sterile loops were used to streak the remaining quadrants of each plate.
  • tissue sample was added with 1 mL of thioglycollate broth to a sterile tissue grinder (Precision® Disposable Tissue Grinder; Covidien, Dublin, Ireland) and ground for one minute or until homogenized.
  • a sterile tissue grinder Precision® Disposable Tissue Grinder; Covidien, Dublin, Ireland
  • One drop of the dissolved tissue sample was transferred to each agar plate and to a microscope slide. Individual, disposable sterile loops were used to streak the agar plates.
  • Four to five drops of the tissue sample were then placed into a test tube of thioglycollate broth.
  • the BAP, MAC, and CNA plates were incubated aerobically at 37 °C. for forty-eight (48) hours and then checked for growth to rule out contamination.
  • the ANA CDC plates with gentamicin disks were kept in sterile bags with a carbon dioxide (CO2) pouch system to maintain anaerobic conditions. Each sterile bag included an oxygen-indicator to ensure anaerobic conditions were met.
  • the ANA CDC plates were incubated at 37 °C. for seven days and then analyzed for P. Acnes. Thioglycollate broth test tubes were sealed with parafilm to protect against contamination. These samples were incubated at 37 °C. for thirty (30) days or until a positive P. Acnes diagnosis could be made. All cultures were checked daily for bacterial growth.
  • a positive culture was defined by growth on the anaerobic plate within seven days and/or if the thioylcollate broth became turbid, and subtyped as P. Acnes within fourteen days.
  • P. Acnes resides in the normal joint, and that it may be a pathologic precursor to shoulder arthritis 15 ' 18 , it is more likely contamination from the dermis.
  • the experiments described herein support the dermis as the primary source of P. Acnes, as adding an agent that crosses the dermis and is toxic to the local bacteria substantially reduced the bacteria that was identified both in the joint and on the skin.
  • BPO is a powerful antimicrobial agent which is directly toxic to both surface and ductal bacteria. Its lipophilic properties permit penetration of the pilosebaceous duct.
  • BPO decomposes to release free oxygen radicals, which have potent bactericidal activity in the sebaceous follicles. 8 ' 10 Given its efficacy, relatively low cost, and low risk of adverse events, BPO was chosen to be used in surgical skin preparation, which has not yet been done.
  • the untreated arm had a significantly higher rate of P. Acnes compared to the BPO treated arm before skin preparation (P 0.039).
  • the lower rate of culture observed may have a few explanations. These patients were all treated with topical BPO on the contralateral arm and may have had some systematic absorption. These patients also had all bathed the morning of surgery, had not been active, and received IV antibiotics.
  • P. Acnes is a significant pathogen with a specific predilection for SSI in shoulder surgery.
  • Current skin preparation with antiseptic skin preparation agents such as for example, aqueous- iodophor, aqueous-chlorhexidine gluconate, alcohol -iodophor, and alcohol-chlorhexidine gluconate are imperfect; residual bacteria are identified on the skin up to 29% of the time at the beginning of the surgical procedure, 63% of the time at the conclusion of surgery in individuals undergoing first time shoulder surgery, and in 70% of dermal biopsy.
  • the high rate of residual bacteria left on the epidermis and dermis both may be the source of infection in susceptible patients, particularly those having procedures with a surgical implant.
  • topical benzoyl peroxide cream substantially reduces the rate at which P. Acnes is identified to 6%, which is no different when compared to control samples.
  • the addition and/or co-administration of benzoyl peroxide to current antiseptic skin preparation agents substantially reduces the rate at which bacteria, such as, for example, P. Acnes, is identified during the perioperative period of an invasive procedure when compared to current antiseptic skin preparation agents used alone.
  • MGHL middle glenohumeral ligament
  • BPO Benzoyl Peroxide
  • This chart depicts bivariate analysis of risk factors associated with subjects with a positive P. Acnes culture within 14 days. There was no significant difference associated with positive culture for age above and below 55 years and history of cortisone injection.
  • SD standard deviation
  • BMI body mass index
  • MGHL middle glenohumeral ligament
  • BPO Benzoyl Peroxide
  • MGHL middle glenohumeral ligament
  • BPO Benzoyl Peroxide
  • This table depicts the rate of positive cultures obtained by location of specimen obtained. The top half of the chart depicts rate of positive culture prior to ChloraPrep® skin preparation.
  • Samples 3 and 4 the non-surgical arm that did not have topical BPO, were significantly greater than the control swab.
  • sample 4 the untreated axilla skin, was significantly greater than sample 1, the BPO treated axilla skin.

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Abstract

La présente invention concerne des compositions et des kits comprenant du peroxyde de benzoyle ou un dérivé de celui-ci et au moins un agent antiseptique de préparation de la peau, qui peuvent être utilisés, par exemple, pour réduire Propionibacterium Acnes (P. Acnes) dans la peau de mammifère (par exemple, la peau humaine) pendant la période périopératoire d'une procédure invasive ; des procédés comprenant l'administration au mammifère (par exemple, un humain) en ayant besoin de compositions comprenant, constituées de, ou essentiellement constituées de peroxyde de benzoyle ou un dérivé de celui-ci et au moins un agent antiseptique de préparation de la peau ; et des procédés de réduction de bactéries, telles que, par exemple, P. Acnes, dans la peau de mammifère (par exemple, la peau humaine) pendant la période périopératoire d'une procédure invasive comprenant l'administration à un mammifère (par exemple, un humain) en ayant besoin d'une première composition comprenant, constituée de, ou essentiellement constituée de peroxyde de benzoyle ou un dérivé de celui-ci et l'administration au mammifère d'une deuxième composition comprenant, constituée de, ou essentiellement constituée d'au moins un agent antiseptique de préparation de la peau.
PCT/US2016/018918 2015-02-20 2016-02-22 Compositions comprenant du peroxyde de benzoyle ou un dérivé de celui-ci et au moins un agent antiseptique de préparation de la peau WO2016134363A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229116A (en) * 1989-11-28 1993-07-20 Edgar Boo E Administration of pharmaceutical agents
US5916882A (en) * 1997-04-08 1999-06-29 Allegiance Corporation Povidone iodine (PVP-I) alcohol gel antimicrobial pre-operative skin preparation
WO2011119247A2 (fr) * 2010-03-23 2011-09-29 Cosmalabs International, Llc Composition topique de soin de la peau
WO2012094009A2 (fr) * 2011-01-06 2012-07-12 CareFusion, Inc. Procédés de réduction des infections du champ opératoire
WO2013028833A1 (fr) * 2011-08-23 2013-02-28 Anthony Natale Systèmes et procédés de traitement d'une infection pathogène

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5229116A (en) * 1989-11-28 1993-07-20 Edgar Boo E Administration of pharmaceutical agents
US5916882A (en) * 1997-04-08 1999-06-29 Allegiance Corporation Povidone iodine (PVP-I) alcohol gel antimicrobial pre-operative skin preparation
WO2011119247A2 (fr) * 2010-03-23 2011-09-29 Cosmalabs International, Llc Composition topique de soin de la peau
WO2012094009A2 (fr) * 2011-01-06 2012-07-12 CareFusion, Inc. Procédés de réduction des infections du champ opératoire
WO2013028833A1 (fr) * 2011-08-23 2013-02-28 Anthony Natale Systèmes et procédés de traitement d'une infection pathogène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MILLETT, PJ ET AL.: "Propionobacter acnes infection as an occult cause of postoperative shoulder pain.", CLINICAL ORTHOPAEDICS AND RELATED RESEARCH., vol. 469, 2011, pages 2824 - 2830, XP019951000, DOI: doi:10.1007/s11999-011-1767-4 *

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